Gujral et al. (1,2) synthesized methaqualone (2-methyl-3-o-tolyl-4-quinazolone) and reported its sedative and hypnotic effect. In addition, it also possesses anticonvulsant, antispasmodic, local anesthetic, and weak antihistaminic properties (3). Unfortunately, the drug has high abuse potential and has been withdrawn from the market in the United States. It is represented by the following formula: ##STR2##
Numerous derivatives of methaqualone have been prepared. For example, 2-methyl-3-(2-trifluoromethylphenyl)-4-quinazolone was synthesized by Klosa and Starke. A comparison of this compound with methaqualone showed lower toxicity and better sedative effect (4). Some 4-oxo-3,4-dihydroquinazolines were prepared. These products exhibited various types of physiological activity (5). Anticonvulsant activity of 2-methyl-3-p-bromophenyl-4-quinazolone has been reported against pentylenetetrazol induced seizures (6). A number of derivatives of 2,3-substituted 4-quinazolones were synthesized. These compounds exhibited antiphlogistic, analgesic, antipyretic, and anticonvulsive effects (7). Bhaduri and Khanna synthesized 2,3-substituted 4-quinazolones and 8-aza quinazolones as potential CNS-depressants (8). Quinazolone hydrazides were synthesized, and these hydrazides exhibited some anticonvulsant activity (9, 10, 11). However, there is still a need for a safe anticonvulsant compound that has limited or no sedative or hypnotic effect.
In order to decrease the hypnotic property and abuse potential of methaqualone and retain the anticonvulsant activity, we attempted to decrease the lipid solubility of the drug by introducing a hetero nitrogen atom in the phenyl ring at position 3, at position 8, or at both positions. We also attempted to decrease lipid solubility by introducing a NH.sub.2 group at position 6 or 7 of the quinazolone nucleus. Several other structural analogs of methaqualone were also prepared and evaluated for anticonvulsant activity. We discovered certain substituted quinazolones with anticonvulsant activity but with limited or no sedative or hypnotic effect.